Schizophrenia is a complex disorder that is characterized by multiple functional and anatomical changes across the neocortex. Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been associated with deficits of working memory, while functional changes in the superior temporal gyrus (STG) have been related to psychosis. In addition, a functional disconnection between the PFC and STG may contribute to the cognitive symptoms of schizophrenia. Although changes in the expression of individual genes have been reported in both STG and PFC, the transcriptome differences across these regions and the relationship between them remain mostly unknown. The presentation of schizophrenia across genders has been associated with differences in age of onset, symptomathology, premorbid history, neuroimaging findings, drug responsiveness and brain structure. Functional and structural studies suggest that gender differences are present in the STG and PFC of subjects with schizophrenia. However, we do not know if these gender differences reflect (or are reflected by) differences in the underlying transcriptomes. This application is focused around two critical questions: 1) Is there a schizophrenia-related expression profile within and across different brain regions and 2) Are schizophrenia-related expression changes different across genders? In this context, we propose to test seven specific hypotheses using 3 specific aims:
Aim 1. Compare gene expression pattern in 12 MALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices.
Aim 2. Compare gene expression pattern in 12 FEMALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices.
Aims 1 and 2 will share the same methodology, and compare the transcriptomes: A) Using whole genome HG_U133A and B Affymetrix microarrays. B) Using custom-made, high-sensitivity polymer cDNA microarrays. These cDNA polymer arrays, involving our proprietary probes (patent application in progress) will allow us an improved and targeted assessment of many transcripts that are too sparse to be detected by the currently available microarrays.
Aim 3. Verify and localize the microarray-uncovered gene expression changes to cell types A) at transcript level using in situ hybridization and B) at protein level using immunohistochemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067234-03
Application #
6932015
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Meinecke, Douglas L
Project Start
2003-07-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$243,393
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Schwede, Matthew; Nagpal, Shailender; Gandal, Michael J et al. (2018) Strong correlation of downregulated genes related to synaptic transmission and mitochondria in post-mortem autism cerebral cortex. J Neurodev Disord 10:18
Korade, Zeljka; Genaro-Mattos, Thiago C; Tallman, Keri A et al. (2017) Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone exposure. J Lipid Res 58:2139-2146
Schmidt, Martin J; Mirnics, Karoly (2015) Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology 40:190-206
Garbett, K A; Vereczkei, A; Kálmán, S et al. (2015) Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors. Transl Psychiatry 5:e523
Brown, J A; Ramikie, T S; Schmidt, M J et al. (2015) Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Mol Psychiatry 20:1499-507
Garbett, Krassimira A; Vereczkei, Andrea; Kálmán, Sára et al. (2015) Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression. Biol Psychiatry 77:256-265
Horváth, Szatmár; Mirnics, Károly (2015) Schizophrenia as a disorder of molecular pathways. Biol Psychiatry 77:22-8
Schmidt, M J; Horvath, S; Ebert, P et al. (2014) Modulation of behavioral networks by selective interneuronal inactivation. Mol Psychiatry 19:580-7
Korade, Zeljka; Mirnics, Károly (2014) Programmed to be human? Neuron 81:224-6
Korade, Zeljka; Xu, Libin; Harrison, Fiona E et al. (2014) Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz syndrome. Biol Psychiatry 75:215-22

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